RESUMO
PURPOSE: Immune checkpoint inhibitors (ICIs) alone or in combination with chemotherapy can improve the limited efficacy of colorectal cancer (CRC) immunotherapy. CX-5461 causes substantial DNA damage and genomic instability and can increase ICIs' therapeutic efficacies through tumor microenvironment alteration. RESULTS: We analyzed whether CX-5461 enhances ICIs' effects in CRC and discovered that CX-5461 causes severe DNA damage, including cytosolic dsDNA appearance, in various human and mouse CRC cells. Our bioinformatics analysis predicted CX-5461-based interferon (IFN) signaling pathway activation in these cells, which was verified by the finding that CX-5461 induces IFN-α and IFN-ß secretion in these cells. Next, cGAMP, phospho-IRF3, CCL5, and CXCL10 levels exhibited significant posttreatment increases in CRC cells, indicating that CX-5461 activates the cGAS-STING-IFN pathway. CX-5461 also enhanced PD-L1 expression through STAT1 activation. CX-5461 alone inhibited tumor growth and prolonged survival in mice. CX-5461+anti-PD-1 or anti-PD-L1 alone exhibited synergistic growth-suppressive effects against CRC and breast cancer. CX-5461 alone or CX-5461+anti-PD-1 increased cytotoxic T-cell numbers and reduced myeloid-derived suppressor cell numbers in mouse spleens. CONCLUSIONS: Therefore, clinically, CX-5461 combined with ICIs for CRC therapy warrants consideration because CX-5461 can turn cold tumors into hot ones.
Assuntos
Neoplasias Colorretais , Inibidores de Checkpoint Imunológico , Humanos , Camundongos , Animais , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Antígeno B7-H1/metabolismo , Naftiridinas , Benzotiazóis , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Microambiente TumoralRESUMO
BACKGROUND AND AIMS: This study aimed to investigate safety and efficacy of silmitasertib, an oral small molecule casein kinase 2 inhibitor, plus gemcitabine and cisplatin (G+C) versus G+C in locally advanced/metastatic cholangiocarcinoma. APPROACH AND RESULTS: This work is a Phase 1b/2 study (S4-13-001). In Phase 2, patients received silmitasertib 1000 mg twice daily for 10 days with G+C on Days 1 and 8 of a 21-day cycle. Primary efficacy endpoint was progression-free survival (PFS) in the modified intent-to-treat population (defined as patients who completed at least one cycle of silmitasertib without dose interruption/reduction) from both phases (silmitasertib/G+C n = 55, G+C n = 29). The response was assessed by Response Evaluation Criteria in Solid Tumors v1.1. The median PFS was 11.2 months (95% confidence interval [CI], 7.6, 14.7) versus 5.8 months (95% CI, 3.1, not evaluable [NE]) ( p = 0.0496); 10-month PFS was 56.1% (95% CI, 38.8%, 70.2%) versus 22.2% (95% CI, 1.8%, 56.7%); and median overall survival was 17.4 months (95% CI, 13.4, 25.7) versus 14.9 months (95% CI, 9.9, NE) with silmitasertib/G+C versus G+C. Overall response rate was 34.0% versus 30.8%; the disease control rate was 86.0% versus 88.5% with silmitasertib/G+C versus G+C. Almost all silmitasertib/G+C (99%) and G+C (93%) patients reported at least one treatment emergent adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib/G+C versus G+C were diarrhea (70% versus 13%), nausea (59% vs. 30%), fatigue (47% vs. 47%), vomiting (39% vs. 7%), and anemia (39% vs. 30%). Twelve patients (10%) discontinued treatment because of TEAEs during the study. CONCLUSIONS: Silmitasertib/G+C demonstrated promising preliminary evidence of efficacy for the first-line treatment of patients with locally advanced/metastatic cholangiocarcinoma.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Humanos , Gencitabina , Cisplatino/uso terapêutico , Desoxicitidina/uso terapêutico , Colangiocarcinoma/patologia , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias dos Ductos Biliares/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.
Assuntos
Neoplasias , Benzotiazóis/uso terapêutico , DNA , Humanos , Naftiridinas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologiaRESUMO
One in 10 independently living adults aged 65 years old and older is considered frail, and frailty is associated with poor postoperative outcomes. This systematic review aimed to examine the association between frailty assessments and postoperative outcomes in patients with vascular disease. Electronic databases - MEDLINE, Embase, and the Cochrane Library - were searched from inception until January 2022, resulting in 648 articles reviewed for potential inclusion and 16 studies selected. Demographic data, surgery type, frailty measure, and postoperative outcomes predicted by frailty were extracted from the selected studies. The risk of bias was assessed using the Newcastle-Ottawa Scale. The selected studies (mean age: 56.1-76.3 years) had low-to-moderate risk of bias and included 16 vascular (elective and nonelective) surgeries and eight frailty measures. Significant associations (p < 0.05) were established between mortality (30-day, 90-day, 1-year, 5-year), 30-day morbidity, nonhome discharge, adverse events, failure to rescue, patient requiring care after discharge, and amputation following critical limb ischaemia. The strongest evidence was found between 30-day mortality and frailty. Composite 30-day morbidity and mortality, functional status at discharge, length of stay, spinal cord deficit, and access site complications were found to be nonsignificantly associated with frailty. With frailty being significantly associated with several adverse postoperative outcomes, preoperative frailty assessments can potentially be clinically useful in helping practitioners predict and guide the pre-, peri-, and postoperative management of frail with vascular disease.
Assuntos
Fragilidade , Doenças Vasculares , Idoso , Idoso Fragilizado , Fragilidade/diagnóstico , Avaliação Geriátrica , Humanos , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Medição de Risco , Fatores de Risco , Doenças Vasculares/cirurgiaAssuntos
Ascite/diagnóstico , Endometriose/diagnóstico , Cistos Ovarianos/diagnóstico , Doenças Ovarianas/diagnóstico , Adulto , Diagnóstico Diferencial , Edema/fisiopatologia , Endometriose/fisiopatologia , Endometriose/cirurgia , Feminino , Humanos , Cistos Ovarianos/fisiopatologia , Cistos Ovarianos/cirurgia , Doenças Ovarianas/fisiopatologia , Doenças Ovarianas/cirurgia , Paracentese , Tomografia Computadorizada por Raios X , Ultrassonografia , Aumento de PesoRESUMO
Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.
Assuntos
Benzotiazóis/farmacologia , Cistadenocarcinoma Seroso/tratamento farmacológico , Dano ao DNA , Naftiridinas/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/metabolismo , Replicação do DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Feminino , Xenoenxertos , Recombinação Homóloga , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Modelos Biológicos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , RNA Polimerase I/antagonistas & inibidores , TranscriptomaRESUMO
RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar-plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable. SIGNIFICANCE: CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.This article is highlighted in the In This Issue feature, p. 983.
Assuntos
Antineoplásicos/uso terapêutico , Benzotiazóis/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Naftiridinas/uso terapêutico , RNA Polimerase I/metabolismo , Transcrição Gênica/efeitos dos fármacos , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzotiazóis/administração & dosagem , Benzotiazóis/efeitos adversos , Benzotiazóis/farmacologia , DNA Ribossômico/genética , Feminino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Naftiridinas/administração & dosagem , Naftiridinas/efeitos adversos , Naftiridinas/farmacologia , Gradação de Tumores , Estadiamento de Neoplasias , Adulto JovemRESUMO
PURPOSE: Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC). EXPERIMENTAL DESIGN: CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model. RESULTS: Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. CONCLUSIONS: These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.
Assuntos
Caseína Quinase II/antagonistas & inibidores , Naftiridinas/farmacologia , Paclitaxel/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Naftiridinas/administração & dosagem , Paclitaxel/administração & dosagem , Fenazinas , Intervalo Livre de Progressão , Neoplasias Gástricas/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/AIM: Casein kinase 2 (CK2) is involved in multiple cellular processes. Furthermore, its overexpression in several human cancers has been associated with tumor progression. In this study, we evaluated the efficacy of the CK2 inhibitor, CX-4945, in gastric cancer cell lines and explored the potential predictive biomarkers for CX-4945 sensitivity. MATERIALS AND METHODS: The sensitivity to CX-4945 was screened in 49 gastric cancer cell lines by the MTT assay. The mRNA and protein expression of CK2 subunits (α and α') were determined using qRT-PCR and western blot. Furthermore, the activity of CK2α was measured by ELISA. Gene expression and mutations were analyzed via whole-exome and RNA sequencing. RESULTS: The sensitivity to CX-4945 was determined by the inhibition rate (%) at the effective dose (10 µM) which ranged from -1% to 89% in 49 gastric cancer cell lines. CK2α', but not CK2α, mRNA expression was correlated with CX-4945 sensitivity. CONCLUSION: In this study, CX-4945 showed modest antitumor efficacy in gastric cancer cell lines. CK2 might represent a potential therapeutic target for gastric cancer.
Assuntos
Naftiridinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/enzimologia , Caseína Quinase II/antagonistas & inibidores , Caseína Quinase II/biossíntese , Caseína Quinase II/genética , Linhagem Celular Tumoral , Humanos , Terapia de Alvo Molecular , Mutação , Fenazinas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/genéticaRESUMO
G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).
Assuntos
Proteína BRCA1/deficiência , Proteína BRCA2/deficiência , Benzotiazóis/farmacologia , Benzotiazóis/uso terapêutico , Quadruplex G , Naftiridinas/farmacologia , Naftiridinas/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Sequência de Bases , Benzoxazinas/farmacologia , Caenorhabditis elegans/efeitos dos fármacos , Linhagem Celular Tumoral , Instabilidade Cromossômica/genética , Dano ao DNA , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , DNA Ribossômico/genética , Feminino , Quadruplex G/efeitos dos fármacos , Genoma Humano , Genótipo , Recombinação Homóloga/efeitos dos fármacos , Humanos , Camundongos , Quinolonas/farmacologia , Saccharomyces cerevisiae/metabolismo , Transcrição Gênica/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVES: To present a unique case where detection of oligoclonal bands in serum led to the diagnosis of human immunodeficiency virus (HIV) infection. METHODS: A 64-year-old man treated for hypertension for 11 years had laboratory tests ordered by his primary care physician, including serum protein electrophoresis (SPE) and serum immunofixation electrophoresis. RESULTS: The total protein serum protein concentration was elevated at 9.6 g/dL. The SPE showed an oligoclonal pattern of multiple discrete bands in the γ region; the concentration of one band was approximately 1 g/dL and that of two bands was approximately 0.5 g/dL each, with multiple smaller overlapping bands at approximately 0.1 g/dL each. All fractions by SPE were within reference intervals except for the γ fraction, which was elevated at 3.4 g/dL. The IFE demonstrated that this oligoclonal pattern was a mixture of multiple bands of immunoglobulin G (IgG)-λ and IgG-κ. The patient's HIV-1 antibody screen and HIV-1 Western blot were positive on three subsequent visits with strongly positive HIV-1 antibody index values of more than 50 (cutoff value of 1.0 for reactivity). CONCLUSIONS: The etiology of HIV-associated clonal immunoglobulin bands is hypothesized to result from chronic antigenic stimulation leading to B-cell hyperplasia. In this regard, hypergammaglobulinemia is a well-known consequence of HIV infection due to B-cell activation, associated with paraproteins, and can be seen at any stage of the disease.
Assuntos
Medula Óssea/patologia , Infecções por HIV/diagnóstico , HIV-1/imunologia , Hipergamaglobulinemia/diagnóstico , Imunoglobulinas/sangue , Bandas Oligoclonais/sangue , Linfócitos B/imunologia , Anticorpos Anti-HIV/sangue , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Hipergamaglobulinemia/etiologia , Imunidade Humoral , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , RNA Viral/sangue , Carga ViralRESUMO
Angiosarcoma is a rare soft tissue tumor of the breast. It occurs in both a primary form without a known precursor, and a secondary form that has been associated to a history of irradiated breast tissue. These forms differ in many ways including median age, precipitating factors, and presentation. Both forms have a malignant behavior and a poor prognosis. The endeavor of this paper is to review what is known about the presentation, diagnostic and therapeutic modalities to date.